Reference : The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prev...

	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Biochemistry, biophysics & molecular biology
	Focus Areas :	Systems Biomedicine
	To cite this reference:	http://hdl.handle.net/10993/37524

Title :	The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by a-PD-L1 or a-IL6 antibodies
Language :	English
Author, co-author :	Rolvering, Catherine [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
	Zimmer, Andreas David [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
	Ginolhac, Aurélien [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
	Margue, Christiane [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
	Kirchmeyer, Mélanie [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
	Servais, Florence [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
	Hermanns, Heike M. [University Hospital Würzburg > Medical Clinic and Policlinic II, Division of Hepatology]
	Hergovits, Sabine [University Hospital Würzburg > Medical Clinic and Policlinic II, Division of Hepatology]
	Nazarov, Petr V. [Luxembourg Institute of Health - LIH > Department of Oncology, Proteome and Genome Research Unit]
	Nicot, Nathalie [Luxembourg Institute of Health - LIH > Department of Oncology, Proteome and Genome Research Unit]
	Kreis, Stephanie [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
	Haan, Serge [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
	Behrmann, Iris [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
	Haan, Claude [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Publication date :	2018
Journal title :	Journal of Leukocyte Biology
Publisher :	Federation of American Societies for Experimental Biology
Volume :	104
Pages :	969-985
Peer reviewed :	Yes
ISSN :	0741-5400
City :	New York
Country :	NY
Keywords :	[en] cytokine ; interferon ; IFN-𝛾 ; IDO-1 ; OSM
Abstract :	[en] Interleukin-27 (IL27) is a type-I cytokine of the IL6/IL12 family and is predominantly secreted by activated macrophages and dendritic cells.We show that IL27 induces STAT factor phosphorylation in cancerous cell lines of different tissue origin. IL27 leads to STAT1 phosphorylation and recapitulates an IFN-𝛾-like response in the microarray analyses, with up-regulation of genes involved in antiviral defense, antigen presentation, and immune suppression. Like IFN-𝛾, IL27 leads to an up-regulation of TAP2 and MHC-I proteins, which mediate increased tumor immune clearance. However, both cytokines also upregulate proteins such as PD-L1 (CD274) and IDO-1, which are associatedwith immune escape of cancer. Interestingly, differential expression of these geneswas observed within the different cell lines and when comparing IL27 to IFN-𝛾. In coculture experiments of hepatocellular carcinoma (HCC) cells with peripheral blood mononuclear cells, pre-treatment of the HCC cells with IL27 resulted in lowered IL2 production by anti-CD3/-CD28 activated T-lymphocytes. Addition of anti-PD-L1 antibody, however, restored IL2 secretion. The levels of other TH1 cytokines were also enhanced or restored upon administration of anti-PD-L1. In addition, we show that the suppression of IL27 signaling by IL6-type cytokine prestimulation— mimicking a situation occurring, for example, in IL6-secreting tumors or in tumor inflammation–induced cachexia—can be antagonized by antibodies against IL6-type cytokines or their receptors. Therapeutically, the antitumor effects of IL27 (mediated, e.g., by increased antigen presentation) might thus be increased by combining IL27with blocking antibodies against PD-L1 or/and IL6-type cytokines.
Funders :	University of Luxembourg Grants ; Deutsche Forschungs Gemeinschaft
Permalink :	http://hdl.handle.net/10993/37524
FnR project :	FnR ; FNR3975937 > Iris Behrmann > HepmiRSTAT > Inflammatory microRNAs in liver cancer > 01/09/2013 > 31/08/2016 > 2012

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